WO1992016545A1

WO1992016545A1 - 6-o-methylerythromycin ester derivative

Info

Publication number: WO1992016545A1
Application number: PCT/JP1992/000288
Authority: WO
Inventors: Toshifumi Asaka; Shigeo Morimoto; Katsuo Hatayama
Original assignee: Taisho Pharmaceutical Co., Ltd.
Priority date: 1991-03-14
Filing date: 1992-03-11
Publication date: 1992-10-01

Abstract

A novel 2'-substituted derivative of 6-O-methylerythromycin A represented by general formula (I), which is a macrolide antibiotic having a remarkably reduced bitterness in administration and an improved in vivo absorbability in peroral administration, or a pharmaceutically acceptable salt thereof. In formula (I), R represents pyridyl.

Description

Description 610—Methyl erythrium Mycinester derivatives Technical field

The present invention relates to a derivative of 6-0-methylerythromycin 、, and more particularly, to a 6-0-methylethyl sullomycin which has a markedly reduced bitterness when taken as a drug and has improved in vivo absorbability. It relates to the compound modified at the 2-position of Mycin A. Background art

Erythromycin or its derivatives used for chemotherapy of various bacterial infections generally have a characteristic bitter taste. Therefore, when these are used as oral medicines, there is a need to make capsules or coated tablets. Furthermore, for children and the elderly who have difficulty swallowing these drugs, it is desirable to make them into solutions or granules, in which case masking did not sufficiently reduce bitterness.

Therefore, in order to solve these problems, various erythromycins which have no bitterness when the drug is administered and exhibit antibacterial activity by returning to the active substance in the living body at the time of absorption or after absorption. Derivatives have been studied and developed. For example, the 2-position conductor of erythromycin is ethyl succinate [Antibiotics and Chemotherapy, Vol. 7, No. 9, No. 4] P. 87 (1957)], Probiotic acid ester lauryl sulfate [Journal of the Americas Pharmaceuticals, Inc. American Pharmaceutica IA ssociation), Vol. 48, No. 11, page 62, pp. 195]], aryl, ethyl and benzyl carbonate esters [antino, thiote Antiqueotics Ann- ua-ua I, Vol. 19533-1954, Vol. 500, page 950 (1954)].

For the 2'-derivative of 6-0-methylerythromycin A, Only two types of acid esters and benzyl carbonates and three types of esters of acetyl, p-pionyl, and ethylsuccinyl (Japanese Patent Application Laid-Open No. 61-199098) are known. .

An object of the present invention is to provide a new 2′-position derivative of 6-0-methylerythromycin A with significantly reduced bitterness when taken and improved in vivo absorbability. Disclosure of the invention

The invention relates to the formula

(Wherein, R represents a pyridyl group.) 6-0-methylerythromycin A derivative or a pharmaceutically acceptable salt thereof.

In the present invention, the pyridyl group means a viridyl-2-yl group, a virid-3-yl group, and a virid-4-yl group.

In the present invention, a pharmaceutically acceptable salt is defined as a contact with a human or a lower animal, such as a human or a lower animal, without undue toxicity, irritation, allergy, etc. within the scope of sound medical judgment. It means a salt that is suitable for use and that is effective for the intended use in chemotherapy and prevention of bacterial infections. They include, for example, acetic acid, propionic acid, succinic acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, cunic acid, stearinic acid, succinic acid, ethyl succinic acid, lactobionic acid, gluconic acid, glucoheptic acid. Acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, 2 — hydro Kissene sulfonic acid, benzene sulfonic acid, noduletoluene sulfonic acid, raurylsulfuric acid, lingoic acid, aspartic acid, glutamic acid, adibic acid, cystine, hydrochloric acid, hydrobromic acid Salts with acids such as, but not limited to, phosphoric acid, sulfuric acid, hydroiodic acid, nicotinic acid, oxalic acid, viric acid, thiocyanic acid, pendecanoic acid, acrylic acid polymer and carboxyvinyl polymer Can be mentioned.

The compound of the present invention can be produced, for example, as follows.

That is, 6—0—methyl erythromycin A in an inert solvent, in the presence of a dehydrochlorinating agent, 2—1 to 3 equivalents of vicoline neuzorechloride, nicotinoid zorechloride or isonicotinoyl laurel, Preferably, it can be produced by reacting with 1.5 equivalents.

As the dehydrochlorinating agent, it is possible to use sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium carbonate, sodium carbonate, triethylamine, or the like. Wear. These are used in an amount of 1 to 10 equivalents to 6-0-methylerythromycin A, and preferably 3 to 5 equivalents in the case of sodium hydrogencarbonate. As the inert solvent, there can be used acetone, ethyl acetate, dichloromethan, cross-linked form, tetrahydrofuran, etc., and preferably, acetone, ethyl acetate, tetraethyl and the like. La Hydrofuran. The reaction time is usually 4 to 8 hours at ambient temperature, but if the progress of the reaction is slow, the reaction is continued for another 2 to 4 days. In some cases, if the progress of the reaction is insufficient, the reaction can be continued by further adding a dehydrochlorinating agent and a compound of the formula i.

The compound of formula I of the present invention can be prepared in the form of tablets, capsules, powders, lozenges, soft Xu, suspensions, solutions and the like, and can be administered orally or parenterally. Each of the above-mentioned preparations contains a commonly used excipient (eg, crystalline cellulose, starch, lactose, etc.), a binder (eg, hydroxypropyl cellulose, polyvinyl alcohol, etc.), a lubricant (eg, magnesium stearate, talc, etc.). Etc.), and can be manufactured by an ordinary method (for example, a method prescribed in the Japanese Pharmacopoeia, Revised 12th).

The dosage of the compound of formula I varies depending on the condition, age, weight, and the like of the patient, but is usually administered to adults in a dose of 50 to 200 mg once to four times a day. The best form to carry out

Hereinafter, the present invention will be described in more detail with reference to Examples.

Example 1

6 — 0—Methylerythromycin A (748 mg) and sodium bicarbonate (336 mg) were suspended in tetrahydrofuran (5 ml), and piconoyl chloride hydrochloride (2 ml) was added to the suspension. 67 mg) and stirred at room temperature for 2 days. To the reaction solution was added ethyl acetate, washed with water, and then with saturated saline. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (elution solvent: methanol: cloth form = 1: 20) to give 6-0-methyl erythromycin. A 2 ′ —bikolinic acid ester (0.85 g) was obtained. This was recrystallized from ethyl acetate-hexane.

m.p. 23 to 2 32

F A B-S m / τ

8 5 3 [Μ Η] +

IR v max (Br) cm " ¹ :

3 4 6 9, 1 7 3 2.1 6 9 3, 1 5 8 5

NR (CDC l ₃ ) δ (ppm):

2.28 (6 H. S), 3.00 (3 H. S), 3.4 (3 H, s),

7.7 (1 H. D d d. J = 8 H z. J = 5 H z. J = 1 H z),

7.8 1 (1 H. D d d, J = 8 H z. J = 8 H z. J = 2 H z),

7.97 to 8.03 (1H.m), 8.77-8.81 (1H, m)

Example 2

6 — O—Methylerythromycin A (50 g) and sodium bicarbonate (16.55 g) are suspended in acetonitrile (450 ml), and the suspension is added to nicotinoyl lip. (1.785 g) was added, and the mixture was stirred at room temperature for 3 days. After the acetone was distilled off under reduced pressure, ethyl acetate was added, and the mixture was washed with water and saturated saline. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a crystalline powder. This was recrystallized from ethyl acetate-hexane to give 10-methylerythromycin A2'-nicotinic acid ester (47.27 g). m.p. 2 2 6 ~ 2 2 6 Ό

F A B — M S m / z:

8 5 3 [MH] ⁺

IR v max (Br) cm * " ¹ :

3 4 7 1. 1 7 3 1, 1 6 9 2, 1 5 9 2

NMR (CDCI ₃ ) δ (ppm):

2.26 (6 H. S), 3.01 (3 H. S), 3.44 (3 H. S),

7.1 (1 H. D d d. J = 8 H z. J = 5 H z. J = 1 H z).

8.31 (1 H. D d d. J = 8 H z. J = 2 H z. J = 2 H z),

8.78 (1 H. D d. J = 5 H z. J = 2 H z),

9.17 (1H.dd.J = 2Hz.J = 1Hz)

Example 3

6-0—Methyl erythromycin A (5.0 g) and sodium bicarbonate (1.68 g) were sprinkled over acetate (70 mI), and Mouth ride hydrochloride (1.779 g) was added, and the mixture was stirred at room temperature for 1 day. Sodium hydrogencarbonate (0.556 g) and isonicotinoyl cucumber ride hydrochloride (0.36 g) were added, and the mixture was further stirred for 4 days. The reaction solvent was distilled off under reduced pressure, and ethyl acetate was added to the obtained residue, followed by washing with water and then with saturated saline. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude crystals were recrystallized from ethyl acetate-hexane to give 6-0-methyl erythromycin A 2 · -isonicotinate (4.18) g) was obtained.

m.p. 2 23-2 25 * C

F A B-M S m / z:

8 5 3 [H] ⁺

IR v max (B r) cm ^-1 :

3 4 6 9, 1 7 3 5, 1 6 9 2.1 5 6 3

NMR (CDCI ₃ ) δ (ppm):

2.30 (6 H-, s), 3.00 (3 H. S), 3.4 (3 H, s),

7. 8 1 (2 H. D d. J = 5 H z. J = 2 H z).

8.78 (2 H. Dd. J = 5 H z, J = 2 H z) Test example

A known ester of the compound of the present invention (samples 1 to 3) and 6-0-methyl erythrocyte mycin A (control samples 1 to 3) as control were suspended in 5% arabia gum water, Male ICR mice (12 mice per group) were orally administered at a dose of 100 mg Z kg. Thereafter, three mice were exsanguinated and killed at predetermined time intervals, and the amount of antibacterial activity in the serum was measured. The antibacterial activity was measured by a paper disk method using Micrococcus luteus / ATCCC 9341 as a test bacterium.

Table 1 shows the results.

Table 1 Antimicrobial activity in serum (μg Zm I)

Sample

30 minutes later 1 hour later 2 hours later 4

5.0 1 2 6 7 3 5 5 2. 3 6

2 3.8 7 3 5 8 3 1 8 2. 2 9

3 5.0 7 5 0 5 3 6 0 3.3 1

Control 1 0.8 6 0 6 3 0 5 9 0.2 6

Control 2 0.05 0 0 3 0 2 6 0.20

Control 3 0.64 0 3 0 0 6 3 1 .4 4 Sample 1: Compound obtained in Example 1

Sample 2: Compound obtained in Example 2

Sample 3: Compound obtained in Example 3

Control 1: 6—0—methyl erythromycin A 2′-ethyl carbonate

Control 2: 6—0-Methyl erythromycin A 2'—benzyl carbonate Control 3: 6—0—Methyl erythromycin A 2'—ethyl ethyl phosphate Availability

According to the present invention, there has been provided a macrolide antibiotic which significantly reduces bitterness when taken and has good bioabsorbability when orally administered.

Claims

The scope of the claims

Expression

(Wherein, R represents a pyridyl group.) 6-0-methylerythmicin A derivative or a pharmaceutically acceptable salt thereof.